NRC-AN-019 chemically known as (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-yl-amino)phenyl]benzamide, is a phenylaminopyrimidine derivative and it has the following structural formula.

NRC-AN-019 is herein incorporated by reference in its totality which exhibits a melting point range between 248-252° C. It shows poor aqueous solubility at physiological pH (0.0066 mg/mL at pH 1.2, 0.0002 mg/mL at pH 2.0 and below detection limit at pH 3.0, 4.0, 5.0, 6.0, 6.8, 7.0, 7.5, 8.0 and water) and consequently resulting in very low oral absorption. Its molecular formula is C25H17F6N5O and its relative molecular mass is 517.44.
It has received “orphan drug designation” from the United States Food and Drug Administration (USFDA) for three indications—glioma (brain tumor), pancreatic cancer and chronic myelogenous leukemia (CML). NRC-AN-019 is a protein-tyrosine kinase inhibitor; it inhibits the abnormal functioning of BCR-ABL tyrosine kinase; Abelson (ABL) tyrosine kinase gene at chromosome 9 and the break point cluster (BCR) gene at chromosome 22, which is produced by the Philadelphia chromosome abnormality found in CML. NRC-AN-019 inhibits cell proliferation and induces apoptosis (programmed cell death) in the BCR-ABL cell lines and in the leukemic cells generated by CML. There has been a great deal of interest in understanding the role of tyrosine-specific protein kinases encoded by the transforming viruses and their normal cellular homologues and exploring their potential as therapeutic targets. Thus, BCR-ABL tyrosine kinase inhibitors have started era of molecular targeted therapy and marked a great milestone in cancer drug discovery.
Novel phenylaminopyrimidine derivatives have been disclosed as inhibitors of BCR-ABL kinase for the therapy of CML in US2007/0232633. The novel intermediates which are useful for the preparation of novel phenylaminopyrimidine derivatives have also been disclosed in the aforementioned patent application. This U.S. Patent application particularly describes novel phenylaminopyrimidine derivatives which can be used in the therapy of CML with pharmaceutically acceptable carriers that are suitable for topical, enteral, for example oral or rectal, or parenteral administration and may be inorganic or organic, solid or liquid. In addition to the active ingredient(s), the pharmaceutical compositions of the mentioned invention may contain one or more excipients or adjuvants. Example 14 of the said patent application discloses capsule formulations, comprising active compounds which are prepared by the process described in the examples 1 and 3 utilizing lactose, polyvinylpyrrolidone, talc, sodium lauryl sulfate, crospovidone and magnesium stearate as excipients. The capsule formulation disclosed in the said patent application was found to have very poor absorption characteristics. Polymorphic forms of NRC-AN-019 have been disclosed in US2008/0306100 and US2009/0227611.
US Patent Application No. US2013/0338180 discloses an oral solution comprising an effective amount of NRC-AN-019 including its pharmaceutically acceptable salts and polymorphs thereof which is intended for self-emulsification upon its contact with the gastro-intestinal fluid. In accordance with the aforementioned oral solution, bioavailability improvement was achieved.
Generally, oral solid dosage forms provide lower oral absorption than oral solution but contrary to that in view of patient compliance, solid dosage forms are generally preferred. Therefore, suitable solid dosage forms have been contemplated to obtain oral absorption of NRC-AN-019 that is as close as possible to the bioavailability obtained from oral solution. On account of patient non-compliance, a need arose to develop an orally administrable formulation for increasing the bioavailability of this novel phenylaminopyrimidine derivative with better patient acceptability.
The oral drug administration is the most generally accepted route of administration for treating diseases. Hydrophobic drugs exhibit poor solubility and release rate when administered as conventional tablets or capsules and thus exhibit lower bioavailability.
NRC-AN-019 is practically insoluble in water. It is soluble in dimethylformamide, dimethylacetamide and dimethyl sulfoxide. NRC-AN-019 presents specific difficulties in relation to solubility and its formulation development. Oral absorption of such insoluble drugs is the key point to be considered in solving the problem of low bioavailability.
The above mentioned problems have been solved by preparing a pharmaceutical composition comprising NRC-AN-019 and at least one polymeric matrix agent in the form of solid dispersion, wherein said solid dispersion can be directly used in the process of the preparation of pharmaceutical composition.